Roles of N-Myc and STAT interactor in cancer: From initiation to dissemination

Pruitt, Hawley C.; Devine, Daniel J.; Samant, Rajeev S.

Residual tumor cells that survive initial chemotherapy and radiotherapy are often slow growing and may exhibit characteristics of stem cells. 41 These cells are phenotypically different from the bulk of the original tumor and contribute to recurrence, dissemination and metastasis. In breast cancer, NMI expression is detected in early stage primary tumors. It is likely that loss of NMI precedes metastatic dissemination of breast tumor cells, as the expression of NMI is significantly lower in primary tumors of patients that have Stage 4 disease. 4 Metastasis of epithelial cancers is a complex process that employs epithelial-mesenchymal transition (EMT), entry into the vasculature (intravasation), survival within the circulation and colonization at a secondary site within a foreign microenvironment. 42 EMT, the initial step of the metastatic cascade, is a developmental phenomenon whereby epithelial cells undergo a phenotypic change characterized by loss of epithelial markers, such as cytokeratins, followed by gain of mesenchymal markers. These phenotypic changes are accompanied by loss of apical-basal polarity, reorganization of the actin cytoskeleton and invasion into surrounding tissue. 43 EMT is controlled by a variety of signaling pathways that converge at the master regulatory transcription factors SLUG, SNAIL, TWIST and ZEB1/2. 44 Silencing NMI in breast cancer cells with inherently epithelial phenotypes caused a morphological change, decreased expression of epithelial markers, as well as an increased expression of master regulators ZEB2 and SLUG. 4 Devine and coworkers showed that NMI inhibits the EMT program by antagonizing TGFb signaling. TGFb stimulation leads to Smad-dependent transcription of the master regulators of EMT, and therefore is a potent inducer of EMT. 45 NMI expression reversed mesenchymal phenotypes of highly invasive breast cancer cells through enhancing STAT5-mediated transcription of SMAD7. 4 SMAD7, the inhibitory SMAD, provides negative feedback regulation on TGFb signaling. 46, 47 Stemness Expression of EMT master regulators increases the expression of cell surface markers CD44 and CD24 which are widely accepted as markers of stem cells. 48 Also, stem cells often express master regulators of EMT. One of the foremost signaling pathways implicated in EMT and stem cell renewal is the Wnt signaling pathway. 49 Wnt signaling, discovered for its role in embryonic development of Drosophila, is essential for stem cell and progenitor cell self-renewal in multiple tissues, including the intestine and mammary glands. 50 The pathway begins at the cell surface, where Wnt ligands bind to a member of the Frizzled family of receptors and either the LRP5 or LRP6 co-receptor. Tri-complex formation leads to the stabilization of cytosolic b-catenin, a transcriptional co-factor that can enter the nucleus, bind to a member of the TCF/LEF protein family and subsequently activate transcription of Wnt target genes. 51 The presence of b-catenin in cadherin-catenin complexes that comprise epithelial cell tightjunctions allows for maintenance of epithelial structure and inhibition of EMT. 52 Accumulation of b-catenin in the nucleus of breast carcinoma cells is associated with poor prognosis. 53 In breast cancer, deregulation of the Wnt pathway is not due to mutation of the intracellular components, as in colorectal cancers. Instead, many breast cancers are dysregulated at other levels of the pathway, such as overexpres-sion of the LRP6 c